Manganese-52: applications in cell radiolabelling and liposomal nanomedicine PET imaging using oxine (8-hydroxyquinoline) as an ionophore

Abstract

The ionophore 8-hydroxyquinoline (oxine) has been used to radiolabel cells and liposomal medicines with ¹¹¹In and, more recently, ⁸⁹Zr, for medical nuclear imaging applications. Oxine has also shown promising ionophore activity for the positron-emitting radionuclide ⁵²Mn that should allow imaging of labelled cells and nanomedicines for long periods of time (>14 days). However, to date, the radiometal complex formed and its full labelling capabilities have not been fully characterised. Here, we provide supporting evidence of the formation of [⁵²Mn]Mn(oxinate)₂ as the metastable complex responsible for its ionophore activity. The cell labelling properties of [⁵²Mn]Mn(oxinate)₂ were investigated with various cell lines. The liposomal nanomedicine, DOXIL® (Caelyx) was also labelled with [⁵²Mn]Mn(oxinate)₂ and imaged in vivo using PET imaging. [⁵²Mn]Mn(oxinate)₂ was able to label various cell lines with moderate efficiency (15–53%), however low cellular retention of ⁵²Mn (21–25% after 24 h) was observed which was shown not to be due to cell death. PET imaging of [⁵²Mn]Mn-DOXIL at 1 h and 24 h post-injection showed the expected pharmacokinetics and biodistribution of this stealth liposome, but at 72 h post-injection showed a profile matching that of free ⁵²Mn, consistent with drug release. We conclude that oxine is an effective ionophore for ⁵²Mn, but high cellular efflux of the isotope limits its use for prolonged cell tracking. [⁵²Mn]Mn(oxinate)₂ is effective for labelling and tracking DOXIL in vivo. The release of free radionuclide after liposome extravasation could provide a non-invasive method to monitor drug release in vivo.